We propose molecular mechanical (energy refinement) quantum-mechanical, statistical mechanical and qualitative model building calculations on nucleic acids, drug-nucleic acid complexes and protein-nucleic acid complexes. Methods to efficiently and practically incorporate the effects of water and counter-ions into the calculations will be developed and used to study the sequence dependent conformations, vibrations and stabilities of fragments of DNA and RNA as well as the thermodynamics of double helix formation. Such methods will also be applied to study the interaction of ethidium bromide, proflavine, 4-Nitroquinoline N-oxide, (4NQ)) daunomycin, actinomycin and netropsin with fragments of DNA. These studies should lead to insight into the drug and sequence dependence on the structures, thermodynamics and kinetics of drug-nucleic acid interactions. In particular, this group of drugs includes classical cationic intercalators (ethidium, proflavine), a non-charged two ring intercalator (4NQO), a complex cationic intercalator (daunomycin), a complex hydrophobically driven intercalator (actinomycin), and a minor groove binder (netropsin). Of this group, 4NQO is a potent carcinogen and daunomycin and actinomycin clinically useful anti-cancer drugs. We will use a novel approach (distance geometry) to determine the physical basis for the neighbor exclusion rule in drug intercalation and the conditions under which it might be violated. Such an analysis of this rule may lead to important insights into the nature of bis-intercalator interactions with DNA and the synergistic effects of multiple drug binding to DNA. Qualitative model building followed by energy refinement will be carried out on protypal protein-nucleic acid interactions and used to try to design a DNA sequence specific major groove drug. DNA intercalators and minor groove binders are well known and characterized, but major groove binders are not.